Updated Pediatric ARV Guidelines

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Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection

What's New in the Guidelines

Key changes made by the Panel on Antiretroviral Therapy and Medical Management of HIV-Infected Children (the Panel) to update the February 12, 2014, Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection are summarized below. Throughout the document, text and references have been updated to include new publications where relevant. Minor changes and edits have been made to enhance clarity and facilitate use of the Guidelines. The Panel has added a new section to address specific issues in antiretroviral therapy (ART) for neonates. All changes are highlighted in the PDF version.

Diagnosis of HIV Infection

Because children with perinatal HIV exposure aged 18 to 24 months may have residual maternal HIV antibodies, the Panel recommends that definitive exclusion or confirmation of HIV infection in children in this age group who are HIV antibody-positive should be based on a nucleic acid test (NAT) (AII).

The AMPLICOR® HIV-1 DNA test, widely used for diagnosis of infants born to HIV-1-infected mothers since 1992, is no longer commercially available in the United States. The Panel cautions that the sensitivity and specificity of non-commercial HIV-1 DNA tests may differ from the sensitivity and specificity of the Food and Drug Administration (FDA)-approved commercial test.

Clinical and Laboratory Monitoring of Pediatric HIV Infection

Because current pediatric HIV classification and thresholds for treatment initiation are based on absolute CD4 cell count, the Panel now recommends that absolute CD4 T lymphocyte (CD4) cell count should be used for monitoring immune status in children of all ages, with CD4 percentage as an alternative (AII).

The Panel has added hepatitis B virus (HBV) screening to the schedule for clinical and laboratory monitoring in Table 3 when considering starting or changing to antiretroviral (ARV) drugs with activity against HBV, specifically lamivudine-, emtricitabine-, and tenofovir-containing regimens.

The Panel has updated recommendations for when to initiate therapy in ARV-naive HIV-infected children to incorporate the updated Centers for Disease Control and Prevention (CDC) Surveillance Case Definition for HIV Infection, which aligns children with adult and adolescent patients. It includes age-specific CD4 values, indicating a preference for the use of CD4 count over CD4 percentage in all ages (see Revised Surveillance Case Definition for HIV Infection at http://www.cdc.gov/mmwr/pdf/rr/rr6303.pdf). Information about HIV infection stage based on age-specific CD4 cell count or percentage is provided in Table 6 and Table 7 lists HIV-related symptoms.

The Panel has now stratified the urgency for initiation of combination antiretroviral therapy (cART), recommending urgent initiation in all children younger than 12 months and in those aged 12 months and older with CDC Stage 3-defining opportunistic illnesses or Stage 3 CD4 counts. The text provides guidance that in situations requiring urgent initiation of treatment, the clinical team should expedite a discussion on adherence and provide increased, intensive follow-up in the first few weeks to support the children and families.

What Drugs to Start: Initial Combination Therapy for Antiretroviral Treatment-Naive Children

The Panel has added integrase strand transfer inhibitor-based regimens as agents to be used in combination with two nucleoside analogue reverse transcriptase inhibitors (NRTIs). Raltegravir can be used in children age 2 years and older and dolutegravir in children aged 12 years and older. Raltegravir is also licensed for infants as young as 4 weeks but the Panel would consider usage only in special circumstances.

The protease inhibitor (PI) atazanavir boosted with ritonavir is now considered an alternative PI in children aged 3 months through 5 years and remains a preferred drug for children 6 years and older.

The two-NRTI combination of zidovudine and lamivudine or emtricitabine is now considered an alternative combination for adolescents older than 13 years.

Specific Issues in Antiretroviral Therapy for Neonates

The Panel has added a new section about ART for neonates to address specific issues raised by the ability to diagnose HIV infection within a few days of birth in conjunction with growing discussion and reports of early intensive ART of HIV-infected infants and infants at high risk of HIV infection.

Available information about dosing and safety of individual ARV drugs in term and pre-term infants is summarized and discussed in the context of the benefits and risks of early intensive treatment.

The Panel cautions that existing pharmacokinetic (PK) and safety data are insufficient for the recommendation of a complete combination antiretroviral therapy (cART) regimen to treat preterm infants and term infants younger than 15 days (until 42 weeks postmenstrual age).

The Panel recommends that neonatal care providers who are considering a three-drug ARV treatment regimen of term infants younger than 2 weeks or premature infants contact a pediatric HIV expert for guidance and individual case assessment of the risk/benefit ratio of treatment and for the latest information on neonatal drug doses. The National Perinatal HIV Hotline (1-888-448-8765), provides free clinical consultation on perinatal HIV care.

Management of Medication Toxicity

Toxicity table sections have been reviewed and updated throughout. Notable changes include newer data on the occurrence and management of central nervous system (CNS) adverse effects of efavirenz and the effects on creatinine determination of newer ARV drugs dolutegravir, cobicistat, and rilpivirine.

Central Nervous System Toxicity: The toxicity table has been updated to reflect recent reports indicating that a greater proportion of patients than previously recognized experience persistent CNS symptoms due to efavirenz and new information about suicidality associated with this drug. Major depression or suicidal thoughts are now specified as psychiatric illnesses warranting cautious use of efavirenz. Explicit recommendation is made to discontinue efavirenz for severe and/or persistent symptoms when a suitable alternative exists.

Nephrotoxic Effects: The toxicity table has been updated to include a section about elevation in serum creatinine with drugs that cause an asymptomatic decrease in renal tubular secretion of creatinine, leading to an increase in measured serum creatinine without a true change in glomerular filtration rate: dolutegravir, cobicistat, rilpivirine.

Modifying Antiretroviral Regimens in Children with Sustained Virologic Suppression on Antiretroviral Therapy

The Panel has added a new bulleted recommendation to emphasize the need to consider past episodes of ARV treatment failure, tolerability, and all prior drug resistance testing results to avoid choosing new ARV drugs for which archived drug resistance would limit activity.

Updated ARV drug information has been incorporated in the text and in Table 14 which provides examples of changes in ARV regimen components that are made for reasons of simplification, convenience, and safety profile in children who have sustained virologic suppression on their current regimen.

Role of Therapeutic Drug Monitoring in the Management of Pediatric HIV Infection

The Panel has added language about consideration of dose adjustment for efavirenz with a known CYP2B6 poor metabolizer genotype in children older than 3 years.

Zidovudine: The panel has updated the dosing table to include the dose for continuation of zidovudine after 4 or more weeks based on gestational age.

Non-Nucleoside Analogue Reverse Transcriptase Inhibitors

Nevirapine: The Panel has provided information about the investigational treatment dose of nevirapine for infants younger than 1 month with a link to the new section, Dosing: Special Considerations: Neonates ≤14 Days and Premature Infants.

Rilpivirine: The panel has updated dosing for adolescents and adults to include switching to rilpivirine in appropriate virologcially-suppressed patients.

Protease Inhibitors

Atazanavir: June 2014, the FDA approved the powder formulation of atazanavir for infants and children 3 months and older who weigh at least 10 kg but less than 25 kg. The Panel provides information about dosing and administration of atazanavir powder and discusses issues related to transitioning from atazanavir powder to capsules. Because there is no FDA approved atazanavir powder dose for the child who reaches a weight of 25 kg and cannot swallow pills, the Panel has provided information about an experimental dose currently under study for children who weigh 25 to < 35kg. Information is also provided about the use of cobicistat tablets for boosting atazanavir in adolescents 18 years and older and adults. Information has also been added about administration and dosing of atazanavir with cobicistat in adolescents and adults.

Darunavir: Information has been added about administration and dosing of darunavir with cobicistat in adolescents 18 years and older and adults.

Integrase Strand Transfer Inhibitors

Dolutegravir: The Panel has provided information about the investigational dose being used in a clinical trial for treatment-experienced children younger than 12 years.

Elvitegravir: A tablet formulation of elvitegravir was FDA approved in September 2014 for adults; it is not approved for children younger than 18 years. The Panel has provided dosing recommendations for the use of elvitegravir in combination with other ARV drugs.

Pharmacokinetic Enhancers

Cobicistat: A new section has been added because cobicistat is now available as a tablet and in combination with atazanavir (Evotaz) or darunavir (Prezcobix) as well as the previously available Stribild (emtricitabine-tenofovir disoproxil fumarate-elvitegravir-cobicistat). Cobicistat is not interchangeable with ritonavir. See dosing information for specific PI and elvitegravir that require cobicistat for boosting.

Ritonavir: Information about ritonavir has been moved because it is used as a PK enhancer of other PI in children and adults and is no longer recommended as an antiviral agent. In adults, ritonavir is recommended as a PK enhancer for use with the integrase inhibitor elvitegravir, when used in combination with another PI.